Drug addiction places tremendous social, medical and economic burdens on society. Recent developments in this area have contributed to the notion that drug abuse is a problem with definable biological underpinnings. Despite this progress, the molecular organizing principles responsible for susceptibility to the initiation and maintenance of drug taking behavior have remained elusive. Modalities for therapeutic management of the condition are also lacking. In this application, we propose to use novel and complementary approaches to identify molecular factors that underlie drug seeking behaviors. We will take advantage of several recently established lines of mice in which different genes involved in monoaminergic neurotransmission have been inactivated. The different lines all show a sensitization to the locomotor enhancing effects of psychostimulants that is similar to that seen after chronic drug treatment. We will use a genome- wide mutational approach (ENU mutagenesis) to screen for second site mutations that modify the phenotype of existing knockout mutations. This approach has been pioneered in other genetic systems where it has proven to be a uniquely powerful tool. We will also characterize mutant mice using neurochemical and biochemical approaches and High Density Oligonucleotide Array technology to characterize gene expression profiles in the central nervous system. This should allow identification of genes involved in stable alterations of the CNS associated with chronic drug exposure.